Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity.
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
Schlapbach
Achim
A
Novartis Institutes for BioMedical Research, global Discovery Chemistry, WSJ-88.508, CH-4002 Basel, Switzerland. achim.schlapbach@novartis.com
Feifel
Roland
R
Hawtin
Stuart
S
Heng
Richard
R
Koch
Guido
G
Moebitz
Henrik
H
Revesz
Laszlo
L
Scheufler
Clemens
C
Velcicky
Juraj
J
Waelchli
Rudolf
R
Huppertz
Christine
C
D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000099190:MAP-Kinase-Activated Kinase 2
D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D011744:Pyrimidinones; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2